Alpha-Lipoic acid-based PPARgamma agonists for treating inflammatory skin diseases

Arch Dermatol Res. 2004 Aug;296(3):97-104. doi: 10.1007/s00403-004-0480-5. Epub 2004 Jun 24.

Abstract

Novel thiazolidinedione derivatives of the potent antioxidant, alpha-lipoic (thioctic, 1,2-dithiolane) acid, were prepared. The prototype N-(2-[4-[2,4-dioxo(1,3-thiazolidin-5-yl)methyl]phenoxy]ethyl)-5-(1,2-dithiolan-3-yl)- N-methylpentanamide (designated BP-1003), and dithioester derivatives thereof were shown to be potent activators of peroxisome proliferator-activated receptor gamma (PPARgamma) (EC(50) range 15-101 nM) and modest activators of PPARalpha (EC(50) 5 microM). Both the relatively hydrophobic dithiolane prototype, BP-1003, and its water-soluble dithioglycinate derivative, BP-1017, were shown to inhibit the proliferation of human keratinocytes and suppress the production of interleukin-2 by human peripheral lymphocytes to a greater extent than the antidiabetic thiazolidinedione, rosiglitazone. Both oral and topical administration of BP-1017 showed significant antiinflammatory effects in the oxazolone-sensitized mouse model of allergic contact dermatitis (ACD). These findings suggest that water-soluble lipoic acid-based thiazolidinediones may be efficacious as oral and topical agents for treating inflammatory skin conditions such as contact dermatitis, atopic dermatitis, and psoriasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Animals
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Cell Division / drug effects
  • Dermatitis, Allergic Contact / drug therapy*
  • Disease Models, Animal
  • Haplorhini
  • Humans
  • Interleukin-2 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / drug effects
  • Mice
  • PPAR gamma / agonists*
  • PPAR gamma / metabolism
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*
  • Thioctic Acid / analogs & derivatives*
  • Thioctic Acid / chemistry
  • Thioctic Acid / pharmacology*

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Interleukin-2
  • PPAR gamma
  • Thiazoles
  • Thioctic Acid